- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03722849
Functional Magnetic Resonance Imaging of ATP Cough in Chronic Cough Patients
A Functional Magnetic Resonance Imaging Study to Investigate ATP-sensitive Cough Neural Pathways in Patients With Chronic Cough Hypersensitivity
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Peripheral effects of ATP via P2X3 receptors
ATP has been shown to be a tussive agent particularly on chronic cough patients who were more sensitive than non-cough subjects to inhaled ATP. ATP has been shown to augment the cough response to capsaicin in patients with asthma. Gefapixant at a single oral dose of 50 mg did not modulate capsaicin cough responses in normal volunteers and chronic cough subjects while inhibiting ATP-induced cough particularly in chronic cough subjects. These observations would suggest that ATP has a direct effect on a subset sensory neurons that evoke coughing through the activation of P2X3 receptors.
The use of fMRI to provide insights into the peripheral and central sites of activation by ATP/P2X3 activation We have generated functional brain imaging (fMRI) data to suggest that the different brain circuits in receipt of nodose and jugular ganglia neuron inputs (as identified in animal studies) are conserved in humans. When inhaled, the tussigenic compound capsaicin (from hot chili peppers) indiscriminately stimulates both nodose and jugular chemosensitive afferents and we have published that capsaicin inhalation produces brain activations in the primary sensory, anterior and mid-insula, cingulate, premotor, motor and orbitofrontal cortices. These regions are presumed to encode perceptual awareness of airway irritation, and the associated emotional, cognitive and behavioral (motor) consequences. For example, activity in the human primary sensory cortex (which receives jugular ganglia inputs in animal studies) correlates with an individual's perception of airway irritation (their perceived need/ urge to cough) while activity in the insula (in receipt of nodose inputs) relates closely to the actual magnitude of the delivered stimulus independent of perception. We have now built upon these published findings by using high resolution brainstem fMRI during the inhalation of ATP (expected to only activate P2X2/3 expressing nodose-derived airway afferents) versus capsaicin (expected to activate both jugular and nodose chemosensitive afferents). Our results are striking and reveal that ATP inhalation evokes an in increased signal level in the brainstem regions corresponding to the nTS, while capsaicin inhalation produces activations in both the nTS and in an area of the dorsal spinal trigeminal nucleus on the lateral margins of the brainstem that contains the paratrigeminal nucleus. Indeed, our healthy participants did not cough as much to ATP compared to capsaicin, consistent with studies cough in animals and humans and the relatively poor cough-evoking properties of ATP in healthy humans. However, the perception of airway irritation was identical between ATP and capsaicin stimuli. We believe that cough production will ultimately be dependent upon activation of the neural circuit that integrates in the paratrigeminal nucleus (i.e.' the jugular afferent pathway) and therefore we hypothesize that there is an upregulation of the capacity of ATP to act via jugular ganglia pathways in chronic cough patients.
The fMRI studies described above provide an exciting opportunity to assess for the first time which primary airway afferent pathways are likely excited or sensitized by ATP and, in turn, what aspects of the central processing of airway sensory information is altered by ATP. We have reported previously that patients with chronic cough display functional brain responses consistent with a state of central sensitization that closely resembles the central sensitization accompanying chronic pain.
We will extend upon these findings by determining whether ATP-sensitive pathways in the brainstem and brain are altered in patients with chronic cough, and in doing so provide insight into whether ATP effects vagal afferent processing through an interaction with nodose and/ or jugular neural pathways.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Victoria
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Parkville, Victoria, Australia, 3010
- The University of Melbourne
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with physician diagnosed chronic refractory cough (cough lasting >8 weeks).
- > 18 years of age
- Must be cognitively impaired
Exclusion Criteria:
- People with contraindications to MRI scanning (i.e. metal implants, claustrophobia).
- History of uncontrolled asthma or chronic respiratory disease (other than refractory cough).
- Evidence of an allergic reaction to capsaicin (chilli).
- Pregnant women.
- Smoking, current or recent history (last 6 months).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Chronic cough participant
Twenty-five (25) Idiopathic chronic cough patients, defined as refractory to disease modifying therapies (eg anti-asthma medications), will be recruited. Participants will attend two sessions. In the first they will inhale in a single breath a nebulized solutions of increasing doses of Adenosine Triphosphate (ATP; 0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants will undergo functional brain imaging (fMRI) for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin. |
Participants will inhale escalating concentrations of Adenosine Triphosphate (ATP) to induce cough and the urge-to-cough
Other Names:
Participants will inhale escalating concentrations of capsaicin to induce cough and the urge-to-cough
Participants will have scans of their brain activity using 3 Tesla (3T) brainstem restricted functional brain imaging (fMRI)
Other Names:
|
Experimental: Healthy control participant
Twenty-five (25) appropriately age and sex matched healthy non-smoking individuals will be recruited as the comparison group. Participants will attend two sessions. In the first they will inhale in a single breath a nebulized solutions of increasing doses of ATP (0.2-300 microM) and capsaicin (0.5-125 microM) to determine their individual cough and urge-to-cough thresholds. In the second session, participants will undergo fMRI for 1 hour while inhaling over 24 seconds randomly administered nebulized solutions of saline, or threshold doses of ATP or capsaicin. |
Participants will inhale escalating concentrations of Adenosine Triphosphate (ATP) to induce cough and the urge-to-cough
Other Names:
Participants will inhale escalating concentrations of capsaicin to induce cough and the urge-to-cough
Participants will have scans of their brain activity using 3 Tesla (3T) brainstem restricted functional brain imaging (fMRI)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Brainstem neural activations
Time Frame: 18 months
|
fMRI will be used to determine the location and magnitude of neural responses in the brain during ATP and capsaicin inhalation.
fMRI non-invasively measures Blood Oxygen Level Dependent (BOLD) signals in the brain which can be used to identify regions of the brain that increase activity associated with the inhaled stimuli.
Comparisons between regional BOLD responses evoked by ATP and capsaicin (compared to saline) will allow the different neural networks involved in cough generation to be explored in healthy and chronic cough participants.
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18 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Behavioral responses
Time Frame: 18 months
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Participant responses (cough and the urge-to-cough) evoked by ATP and capsaicin will be measured by counting audible coughs and by asking participants to rate their perception of urge-to-cough using visual analogue scales (VAS).
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18 months
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Stuart Mazzone, PhD, University of Melbourne
Publications and helpful links
General Publications
- Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008 Apr 19;371(9621):1364-74. doi: 10.1016/S0140-6736(08)60595-4.
- Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, Smith JA, Parker SM, Chung KF, Lai K, Pavord ID, van den Berg J, Song WJ, Millqvist E, Farrell MJ, Mazzone SB, Dicpinigaitis P; Chronic Cough Registry. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014 Nov;44(5):1149-55. doi: 10.1183/09031936.00217813. Epub 2014 Sep 3.
- Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013 Jul;1(5):414-22. doi: 10.1016/S2213-2600(13)70043-2. Epub 2013 May 3.
- Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med. 2007 Aug 15;176(4):327-32. doi: 10.1164/rccm.200612-1856OC. Epub 2007 Jun 15.
- Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 2016 Apr;71(4):323-9. doi: 10.1136/thoraxjnl-2015-207425. Epub 2016 Feb 9.
- Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015 Mar 28;385(9974):1198-205. doi: 10.1016/S0140-6736(14)61255-1. Epub 2014 Nov 25.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Respiratory Tract Diseases
- Respiration Disorders
- Signs and Symptoms, Respiratory
- Cough
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Vasodilator Agents
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Purinergic Agents
- Dermatologic Agents
- Antipruritics
- Purinergic P1 Receptor Agonists
- Purinergic Agonists
- Adenosine
- Capsaicin
Other Study ID Numbers
- Study 58136
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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